Background: We have previously reported significantly improved disease-free survival (DFS) in premenopausal patients with endocrine-responsive early breast cancer receiving adjuvant zoledronic acid (ZOL) in ABCSG-12 (Gnant M, et al. NEJM. 2009;360:679–91). Other trials, such as ZO-FAST and the postmenopausal (>5 yr) subset analysis of AZURE, have demonstrated similar anticancer effects with ZOL. Now with >6 yr of follow-up in ABCSG-12, we report an overall survival (OS) benefit and preplanned subgroup analyses that more precisely define interactions between the ZOL benefit and patient/tumor characteristics.
Methods: Premenopausal women with endocrine-receptor-positive early stage breast cancer (N = 1,803) were randomized to ovarian function suppression with goserelin (3.6 mg q28d) and tamoxifen (TAM; 20 mg/d) or anastrozole (ANA; 1 mg/d) ± ZOL (4 mg q6mo) for 3 yr. Endpoints included DFS and OS, both analyzed using logrank test and Cox models.
Results: At median follow-up of 76 mo, patients receiving ZOL had a significant 27% reduction in the risk of DFS events (HR = 0.73; Cox P = .022) and a significant 41% reduction in the risk of death (HR = 0.59; Cox P = .027) vs no ZOL. Multivariate analyses showed a strong interaction between ZOL and patient age, but did not show any interactions between ZOL and ANA/TAM or any classic tumor parameter (eg, T, N, grade, ER). Among patients > 40 yr of age (n = 1,390) with presumed complete ovarian blockade, ZOL significantly reduced the risk of DFS events by 34% (HR = 0.66; Cox P = .014) and the risk of death by 49% (HR = 0.51; Cox P = .020); however, there were no significant DFS or OS benefits in patients <40 yr of age. Currently, all patients have completed 3 yr of ZOL and are in the follow-up phase with no reported cases of osteonecrosis of the jaw or renal failure. Additional analyses at a median follow-up of approximately 84 mo are planned for late 2011 and will be presented, providing additional insights into disease recurrence patterns with and without ZOL.
Conclusions: Long-term follow-up of ABCSG-12 (76 months) confirms and extends previous results seen at 48 mo and 62 mo follow-up, and suggests that anticancer benefits of adjuvant ZOL result in highly significant DFS and OS benefits mainly in patients with a low-estrogen environment (ie, ovarian suppression and age >40 yr). These results are consistent with the significant DFS and OS improvements seen in the postmenopausal (>5 yr) cohort of the AZURE trial, and suggest that both estrogen deprivation and reduction of bone-turnover-derived growth factors in the bone marrow microenvironment are needed for sufficient suppression of dormant micrometastases. Taken together with the previously demonstrated bone-protective effects of ZOL, these DFS and OS benefits strongly suggest that adding ZOL to adjuvant endocrine therapy should be considered for premenopausal women with endocrine-receptor-positive early breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S1-2.